Disease Information

Mitochondrial Diseases can be classified in a number of different ways.

Often clinicians will refer to 'mitochondrial syndromes' which are names given to a group of patients with similar symptoms and presentation of disease.

The following section gives detailed information on specific mitochondrial syndromes and has been taken directly from the Wellcome Trust Centre for Mitochondrial Disease Research. It is not an exhaustive list but covers the most common syndromes.

This guidance is intended as general advice and it is important to remember that symptoms of Mitochondrial Disease vary hugely from person to person, even within the same mitochondrial syndrome.

Alper's Disease

Alper's disease is a Mitochondrial Disease that affects the brain and liver. Symptoms of Alper's disease include severe epilepsy, loss of developmental skills and liver failure.

Who does it affect?

Alper's disease is a rare condition that generally affects young children (6 months to 3 years), but some older children and young adults may be affected by severe epilepsy and liver disease due to a fault in the same gene that causes Alper's. Typically, a young infant develops normally at first and gains weight and skills appropriately.

At around 12 months old seizures begin and these are often very difficult to control. Seizures may be generalized, where they involve all four limbs, or focal, where a single limb or one side of the body jerks repeatedly. The jerks are sometimes referred to as ‘myoclonic jerks’. The onset of these seizures is associated with a slowing in development and often there is a loss of previously gained skills (regression).

What causes Alper's?

Alper's is caused by a fault in polymerase gamma, an enzyme that allows the mitochondrion to make its own DNA (mitochondrial DNA or mtDNA). This defect was not discovered until 2004 when researchers found faults in a gene called POLG, which contains the genetic code for polymerase gamma. In Alper's syndrome the faulty polymerase Ggamma does not make sufficient mtDNA in liver or brain – these organs are depleted of mtDNA.

How's is Alper's inherited?

Alper's is inherited in an autosomal recessive fashion which means if both parents carry a faulty copy of the gene, then they have a 1 in 4 chance of having an affected child.

Can Alper's be treated?

There is no specific treatment for Alper's disease, but symptoms can be relieved to an extent with anticonvulsants. It is important that Sodium Valproate is avoided as this commonly used anticonvulsant can bring on the liver failure. Liver transplant has proved unsuccessful in patients with Alper's disease.

Can Alper's be prevented?

If the genetic faults are present, then there is nothing that can be taken during pregnancy or given to the infant that will prevent Alper's occurring.

However, once the faults in POLG have been identified, it is possible to offer prenatal testing in the next pregnancy. This form of prevention is only suitable for those people who would consider termination, and would usually be done after 10-12 weeks of the pregnancy by testing a small number of cells removed from the placenta (known as chorionic villus biopsy.)

The POLG gene is examined in this biopsy to see which copies have been inherited. If both faulty copies have been inherited then termination of the pregnancy is offered. In the UK there are 3 centres in Newcastle, London and Oxford that offer this genetic testing service.

Research Questions

We know that Alper's disease is caused by faults in the POLG gene, but at present there is much we do not understand about Alper's such as:

  • How common is Alper's?
  • Why are the liver and brain cells of young children particularly affected?
  • Why do some genetic faults in POLG lead to milder problems with a later onset?
  • How do the mutations in POLG lead to cells not working properly?
  • Why are some parts of the brain more affected than others?
  • How does Alper's compare to other forms of mtDNA depletion involving liver and brain?

These are just some of the questions that researchers are, or will be, trying to answer so that we can understand the mechanisms that cause Alper's diseases. Only through understanding the mechanisms of a disease can we begin to plan effective treatments.

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Mitochondrial DNA Depletion Syndrome (MDDS)

The term depletion refers to the markedly decreased amount of mitochondrial DNA found in muscle, liver and brain tissues in these disorders. These are severe disorders presenting in early infancy or childhood with profound weakness, encephalopathy, seizures and liver failure.

In one form of ‘hepatocerebra’ depletion known as Alper's disease or Progressive Neuronal Degeneration of Childhood (PNDC), explosive onset of seizures, developmental delay and spasticity are followed some variable time later by catastrophic liver failure. In the ‘myopathic’ form of depletion, profound weakness impairs mobility and eventually involves respiratory muscles leading to severe difficulty in breathing.

A number of genes have been associated with specific variations of the depletion syndromes: myopathic (TK2); hepatocerebral (DGOUKPOLG1) and encephalomyopathic (SUCLA2). If a fault in one of these genes is identified as the cause of disease, it could then be identified during future pregnancies by testing a small number of cells removed from the placenta (known as chorionic villous biopsy) or amniocentesis.

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Leigh Syndrome

Leigh disease (syndrome) is named after the pathologist (Denis Leigh) who first described the disease. The condition can be due to a variety of genetic faults in either nuclear or mitochondrial DNA and so Leigh’s disease can be inherited in many different ways.

All of the mutations disrupt the primary aim of the mitochondrion, which is to convert energy into a form that the cell can use. Characteristic patterns of brain involvement on an MRI scan, along with typical clinical findings, usually suggest the diagnosis, and a lumbar puncture may be helpful in confirming a disorder of mitochondrial function (raised cerebrospinal fluid lactate).

Muscle (and skin) biopsy may be helpful in further identifying the cause, but sometimes no biochemical defect of the mitochondria can be demonstrated.

Children with Leigh disease are often weak and floppy, but this may not be obvious until they are several months old. Swallowing, breathing, movement and posture may be particularly affected, as the disorder involves parts of the brain responsible for these functions.

Characteristically, development is said to regress, that is acquired skills such as independent sitting are lost. Sometimes this occurs in conjunction with an otherwise minor illness such as a ‘cold’, sore throat or ‘tummy upset’. Following recovery from the illness there may be recovery of some of the skills lost. Children with Leigh disease may deteriorate in this way over many years, or they may follow a more rapidly progressive decline over a period of months.

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Leber's Hereditory Optic Neuropathy (LHON)

This is the commonest of the Mitochondrial Diseases. Ninety five percent of patients carry one of three specific genetic faults (called point mutations) in their mitochondrial DNA. In the majority, this is inherited from the mother but sometimes the mutation arises for the first time in the patient. Although both men and women can have the mutation, more men go on to have symptoms.

The disease primarily affects the optic nerve. This is the large nerve that leaves the back of each eye to carry visual information to the brain. Patients usually first notice problems with their vision in their twenties or thirties. The first symptoms are of blurring of central vision and loss of colour vision.

Often this starts in just one eye, but in the vast majority the other eye will also be affected within six months. The eyes are not usually painful. Eventually vision may be limited to being able to make out rough shapes or to count fingers only.

No specific treatment exists but there is thought to be an increased risk of patients with LHON developing blindness if they also smoke and drink excess alcohol. The main thrust of treatment is therefore to identify those family members who carry the mutation to advise them to avoid these extra risks. For patients who already have symptoms treatment involves the provision of visual aids.

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MELAS - Mitochondrial Encephalomyopathy, Lactic Acidosis and stroke like episodes; MIDD - Maternally Inherited Diabetes and Deafness; m.3243A>G Mutation

This is one of the most common causes of mitochondrial disease. Patients with this genetic fault (mutation) have variable disease manifestations ranging from no symptoms at all, to being quite severely affected with the syndrome called MELAS, the short name for a collection of symptoms called mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Less than 10% of people with the m.3243A>G mutation will have MELAS. Often patients present with diabetes and deafness due to this mutation and a syndrome known as MIDD (maternally inherited diabetes and deafness).

Why is it so variable?

Patients with this mutation in their mitochondrial DNA have the mutation present in heteroplasmic form. This means that there is a mixture of good and bad mitochondrial DNA within your body and it tends to be the ratio of good to bad mitochondrial DNA that decides the severity of your symptoms. In other words, if you have a lot of good mitochondrial DNA you are unlikely to develop severe symptoms.

If you have a lot of bad mitochondrial DNA then you do tend to develop more symptoms and the disease might be more serious. However, it is only a guide and it has been stressed throughout this website that there is an enormous amount of variation between different individuals even with the same level of mutation and even within families.

Is the m.3243A>G mutation passed down through families?

In some patients, this mutation seems to be a sporadic event, in other words there is no family history of the mutation and the mutation cannot be detected in any of the relatives. However, in most patients, this is an inherited disorder, which is only passed down from mother to child (maternal inheritance).

There is no history of any transmission through the father, and so males with the m.3243A>G mutation cannot pass this to their children. Mothers who carry the mutation are also heteroplasmic (the mixture between good and bad mitochondrial DNA) and are at risk of transmitting the mutation to their children. The real difficulty here lies in the fact that it is currently very hard to predict what level of good and bad mitochondrial DNA will be in the child.

This is because of a complicated process called the mitochondrial bottleneck, which happens during development of a woman’s eggs. This bottleneck means that there is considerable variation between different children from the same mother. We urge mothers who are concerned about transmitting mitochondrial DNA mutations to their children, to seek specialist genetic counselling to discuss this in more detail.

What are the clinical features of the m.3243A>G mutation?

The clinical features associated with this mutation can, as stated above, be very variable. We have a number of individuals who clearly carry the mutation who are completely asymptomatic. Other patients have very, very mild symptoms, such as very mild deafness requiring no treatment. It is important that carriers of m.3243A>G have regular checks for diabetes which can be arranged through their GP.

These patients might not be aware that they had the mutation apart from the fact that they were family members of somebody who had more serious disease. Some people with the m.3243A>G mutation also develop diabetes and deafness, ultimately requiring the use of a hearing aid or requiring insulin to control their diabetes, a condition known as MIDD.

Other patients have more severe involvement with muscle weakness, sometimes affecting the peripheral muscles and sometimes affecting the muscles around the eyes. Finally there is a group of patients who do develop the MELAS syndrome, which is associated with episodes of encephalopathy.

Encephalopathy is the medical term for an episode that disturbs brain function. These disturbances can take the form of stroke-like episodes and/or seizures. This is a much more troublesome and difficult group of symptoms to control and clearly have a significant effect on people’s lifestyle.

Are other tissues involved other than those for which we see a neurologist?

Yes, other tissues can be involved. As indicated above diabetes is a very common symptom in patients with the m.3243A>G mutation and it is advisable that patients see a diabetologist (doctor specialising in diabetes).

Other common problems that we see in our patients are poor bowel function, which often leads to either the irritable bowel disease or severe constipation. This can be quite uncomfortable for patients and we do recommend a good diet, adequate fluid intake and regular laxatives.

Patients can also develop problems with their heart where they get a slightly enlarged heart or a heart that does not function properly (cardiomyopathy) or changes in the rhythm of their heartbeat. This is something that should be monitored on a regular basis and if carefully monitored can probably be helped by early intervention with drugs which slightly lower blood pressure, lower the load on the heart or regulate the heart rhythm.

Treatment of m.3243A>G Is there anything that can be done to help patients with the m.3243A>G mutation?

A key point is for patients to know that they harbour the mutation and to carry information about it with them, in case they need to consult out-of-hours medical services who are unfamiliar with the disorder. Treatment takes several forms in patients with this condition. One of the most important aspects is to make sure that we pick up any complications of the illness at an early stage. For example, referral to an audiology department for hearing assessment may be appropriate and it is extremely helpful to have hearing aids in patients that are suffering from deafness.

It is also worth patients being aware that they have a tendency to develop diabetes and therefore having a good diet and monitoring of blood sugar is an important component of trying to prevent the development of diabetes. If diabetes does develop, then it should be treated as with other patients with diabetes although probably without the early use of a drug called Metformin.

For the bowel symptoms, we do suggest good diet and laxatives as discussed above. We suggest early intervention with drugs for heart problems, which lower blood pressure and reduce the load on the heart.

If patients develop seizures, then these should certainly be treated. There are many different anticonvulsants and no specific anticonvulsant has been shown to be more effective. However, there is good reason to not use the anticonvulsant drug called Sodium Valproate or Valproic Acid.

For the episodes of encephalopathy or stroke-like episodes, there is no really well defined way to treat these conditions at present. There have been trials of a drug called L-Arginine in Japan but it is still uncertain as to whether or not this is beneficial to patients.

In our own centres we try to ensure that patients have adequate fluids, that any infections are treated promptly and that seizures are treated aggressively. An EEG and brain MRI should be performed if possible.

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MERFF - 8344A>G Mutation

This is also a common genetic fault causing Mitochondrial Disease. When present it frequently runs in families, showing a pattern of maternal inheritance. In patients with this particular mitochondrial DNA mutation, there are very variable clinical features.

It is important to recognise that there are patients who carry this mutation who are clinically unaffected, whereas others might develop much more severe disease associated with epilepsy, muscle weakness and unsteadiness.

The reason for the difference between the clinical symptoms relates to the fact that there is a mixture of good and bad mitochondrial DNA in all patients with the 8344A>GMERRF mutation. In the presence of high amounts of faulty or abnormal mitochondrial DNA, patients are much more likely to develop symptoms compared to those that only have a very small amount of this particular mitochondrial DNA mutation.

The clinical features that patients experience with this mutation are predominantly neurological. Patients often develop myoclonic epilepsy. Myoclonus is a brief jerk that often happens first thing in the morning and can be a run of jerks. These jerks are sudden in onset and not necessarily associated with a loss of consciousness.

In some patients there is also seizures and thus they have not only myoclonic epilepsy, but generalised tonic-clonic seizures. Patients may also develop quite a lot of muscle weakness such that they will have difficulty getting up from a squatting position or difficulty drying or washing their hair. Patients also develop symptoms of unsteadiness (ataxia).

This unsteadiness can make walking quite tricky and certainly it makes it difficult performing fine tasks at home. This can be quite a disabling feature in some patients but certainly is not present in many patients with the MERRF mutation. Patients may also develop symptoms associated with a slight loss of memory. This is particularly troublesome for patients in terms of short- term rather than long-term memory. Again, this is a feature which is only present in patients who tend to have severe disease.

Some patients develop a curious phenomenon, which is associated with the development of fat deposits (lipoma) in and around the back of the neck. This is a feature which is usually only seen in patients with the 8344A>G MERRF mutation.

Treatment for patients with the 8344A>G MERRF mutation really involves trying to make sure that we minimise the impact of the disease on people’s lives. Certainly it is important to make sure that people have adequate treatment for their seizures, both the myoclonic jerks and the tonic clonic seizures.

The myoclonic jerks are probably best treated with a drug called Lamotrigine or Levetiracetam. We do not advise patients to take a drug called Sodium Valproate which is used in the treatment of myoclonic seizures due to other conditions. Lamotrigine and Levetiracetam may well be valuable in controlling the generalised tonic clonic seizures although other drugs used to treat epilepsy might also be helpful.

At present there is relatively little that we can do to help with the unsteadiness and the muscle weakness. It is important that people get appropriate aids in their home to make life somewhat easier.

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MNGIE - Mitochondrial Neuro-Gastro-Intestinal Encephalopathy

This is a rare mitochondrial condition which is due not to a defect in mitochondrial DNA but due to a defect in an enzyme called thymidine phosphorylase. As this is not inherited through the mitochondrial DNA, the disease only occurs if both parents carry a faulty gene, giving the patient two bad copies of the thymidine phosphorylase gene. This is called an autosomal recessive pattern of inheritance and more information on this can be found in the Q&A section of this website.

MNGIE presents predominantly either with disturbances of bowel function or with weakness that is largely due to damaged nerve supply. It is quite variable in the severity of the illness with some patients developing quite severe disease early in life, whereas others may develop symptoms much later in life. The disturbance of bowel function can be quite severe, as can the muscle weakness and it may lead to significant difficulties with memory.

The diagnosis of MNGIE is made by measuring thymidine levels in the blood and urine. This is often then confirmed by direct measurements of the enzyme thymidine phosphorylase and possibly even finding the genetic faults in DNA samples.

At present this condition remains very difficult to treat, although a series of innovative experiments are being performed at Columbia University in New York by Dr Michio Hirano and in London by Dr B Bax to determine whether or not specific treatments are possible for this condition.

It is likely that if you do have this condition, your doctor would be in touch with these doctors about any new therapy for this condition and it may be that you will be asked to take part in any clinical trials if you felt this would be helpful for your condition.

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Multiple Mitochondrial DNA Deletions

“Multiple mitochondrial DNA Deletions” refers to different sized pieces of mitochondrial DNA that are missing. The genetic problem here is often inherited, but is not due to a genetic fault (mutation) in mitochondrial DNA.

The defect can occur in one of a number of nuclear genes that control the maintenance, repair or supply of building blocks for mitochondrial DNA. Faults occur quite frequently in mitochondrial DNA, but are usually quickly corrected.

If they are not corrected, then breaks or “deletions” can occur. Currently mutations in three different genes (POLG 1, ANT 1and Twinkle ) are known to cause multiple deletions and are associated with a particular syndrome known as Chronic Progressive External Ophthalmoplegia Plus (CPEO+).

Patients with this syndrome have difficulty with eye movement and drooping eyelids and in this respect are very similar to patients with single deletions. Complications with swallowing, heart problems, weakness and exercise intolerance may also occur. Additional problems include difficulty with balance and sometimes altered or absent sensation in the hands and feet.

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NARP - Neurogenic Weakness, Ataxia and Retinitis Pigmentosa

This syndrome describes a group of patients who have a combination of features including weakness, unsteadiness of movement, impaired sensation (neuropathy) and visual disturbance. The weakness is usually found in the muscles around the large joints such as the hip and shoulder, rather than the hands or feet (proximal myopathy).

Additional features include developmental delay or dementia and those children with very high levels of mutated mitochondrial DNA develop Leigh syndrome.

The mutations responsible for NARP are found in the ATPase genes of mitochondrial DNA (maternally inherited) and two of the most commonly reported sites are8993T>G/C and 9176T>G/C.

These mutations affect complex V, responsible for the final step in the energy conversion process. Routine testing of muscle will often not reveal any abnormality, because activity of complex V is difficult to demonstrate in the tests that we do. If we suspect NARP from the information we gather by talking to and examining the patient, then we identify the coding sequence in the ATPase genes and compare it to normal.

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Large Scale mitochondrial DNA Deletions - Kearn's-Sayre Syndrome and Pearson's Syndrome

The term single deletion describes a piece of DNA that is missing from lots of copies of mitochondrial DNA in each cell. This is usually not an inherited condition, but one that occurs by chance (sporadic).

The rare families with more than one affected member almost always have additional more complex DNA features. Most often, patients with single deletions experience difficulty with eye movement (chronic progressive external ophthalmoplegia or CPEO) and develop droopy eyelids on one or both sides, beginning in early middle-age.

Occasionally, patients may also have swallowing problems, palpitations and in common with other Mitochondrial Diseases, weakness and fatigue.

In a minority of patients with single deletions, the onset of disease is much earlier and may even occur in infancy or the newborn period. When this occurs, the condition is known as Pearson’s syndrome and this is quite different from the adult onset disease.

Development of droopy eyelids, difficulty with eye movement, swallowing difficulties and heart problems before the age of 20 years is yet another form of this disease, known as Kearns-Sayre Syndrome (KSS). In both Pearson’s syndrome and KSS, the amount of deleted mitochondrial DNA is very high in proportion to the amount of remaining normal mitochondrial DNA.

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