Mitochondrial Syndromes

Symptoms of mitochondrial disease vary hugely depending on the actual syndrome or underlying genetic mutation that has caused it.

The following information gives detailed information on specific mitochondrial syndromes and has been taken directly from the Wellcome Centre for Mitochondrial Research website.

Alpers' syndrome

Alpers’ syndrome is a mitochondrial disease that is part of a larger group of conditions collectively known as mitochondrial DNA depletion disorders. It is most often caused by mistakes in the DNA of a gene called POLG (pronounced “pawl-gee”) and is part of a spectrum of POLG-related diseases. There are a number of other, extremely rare, genetic causes of Alpers’syndrome. The three major clinical features associated with Alpers’ syndrome are severe epilepsy, loss of developmental skills (developmental regression) and liver failure.

Who does it affect?

Dr Bernard Alpers first described this very rare condition in young children under the age of 3 years. Since his first description, it has now been reported to also affect older children, adolescents and young adults.

What are the clinical features?

Typically, a young infant develops normally at first and gains weight and skills appropriately. Between 6 and 12 months old seizures begin, which are often very difficult to control with anticonvulsant drugs. 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 loss of previously gained skills.

What causes Alpers’ syndrome?

Alpers’ syndrome is most often caused by a genetic mistake in a gene called POLG. This gene provides the instructions needed to make a protein called polymerase gamma, which is responsible for “reading” sequences of mitochondrial DNA (mtDNA) and using them as a template to produce more mtDNA within the mitochondria. If the polymerase gamma doesn’t work properly due to mutations within the POLG gene, this can lead to a reduction in the amount or quality of mtDNA in affected tissues. In Alpers’ syndrome, the faulty polymerase gamma does not make sufficient mtDNA in liver or brain meaning that these organs are depleted of mtDNA. Other, much rarer causes of Alpers syndrome have been reported including genetic mistakes in genes involved in the process of making mitochondrial proteins such as FARS2, NARS2 and PARS2.

How is Alpers’ syndrome inherited?

Alpers’ syndrome is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the faulty gene to develop the condition. Typically, each parent carries one copy of the faulty gene but they do not show signs or symptoms of the condition because they also have a second, normal copy of the POLG gene, which is sufficient to maintain health. There is a 1 in 4 chance of these parents having an affected child who inherits both copies of the faulty gene (one from each parent).

Can Alpers’ syndrome be treated?

There is no specific treatment for Alpers’ syndrome 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 liver failure in Alpers’ syndrome. Liver transplant has proved unsuccessful in patients with Alpers’ syndrome.

Can Alpers’ syndrome be prevented?

If the genetic mistakes are present, then there is nothing that can be taken during pregnancy or given to the infant that will prevent Alpers’ syndrome occurring.

However, once a genetic mistake in POLG has been identified, there are reproductive options that can be offered to prevent Alpers’ syndrome in the next pregnancy. One option is prenatal testing. 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 chorionic villus biopsy.

The POLG gene is examined in DNA from the biopsy to see which copies have been inherited. If both faulty copies have been inherited then termination of the pregnancy is offered. This type of prenatal testing is also available for other genetic causes of Alpers’ syndrome.

Another reproductive option is preimplantation genetic diagnosis (PGD). This is an IVF-based technique that involves examining the POLG gene in DNA taken from early embryos growing in an IVF lab to see which copies have been inherited. The aim is to identify an embryo that does not carry the genetic mistakes that cause Alpers’ syndrome. If such an embryo is identified, it can be transferred to the womb to try and establish a pregnancy.

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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 Alpers’ 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 mutation in one of these genes is identified as the cause of disease, it could then be identified during future pregnancies by 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 mutations 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 MRI scan along with typical clinical findings usually suggest the diagnosis and 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 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 3243A>G Mutation

This is one of the most common causes of Mitochondrial Disease. Patients with this mutation have variable disease manifestations ranging from no symptoms at all, to being quite severely affected with the syndrome called MELAS , this is the short name for a collection of symptoms called mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.

Why is it so variable?

Patients with this mitochondrial DNA mutation 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 there is an enormous amount of variation between different individuals even with the same level of mutation and even within families.

Is the common MELAS 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 therefore males with the 3243A>G mutation cannot transmit this to their offspring. 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 difficult to predict what the level of good and bad mitochondrial DNA will be in the child.

This is because of a complicated process called the mitochondrial bottleneck in the formation of a lady’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 offspring to seek specialist genetic counselling to discuss this in more detail.

What are the clinical features of the 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 perhaps with a tendency to have diabetes or very mild deafness requiring no treatment.

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 3243A>G mutation, also develop diabetes and deafness ultimately requiring the use of a hearing aid or requiring insulin to control their diabetes.

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 really 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 3243. 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 under these circumstances both a good diet 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).

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 or lower the load on the heart.

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

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, 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 laxative and for the heart problems we suggest early intervention with drugs, 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. 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 centre we try to ensure that patients have adequate fluids, that any infections are treated promptly and that they are investigated with an EEG to make sure that they are not having constant seizures. Any seizures that develop are treated very aggressively to stop the seizures becoming much worse and perhaps leading to stroke-like episodes.

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MERRF - 8344A>G Mutation

Myoclonic epilepsy with ragged red fibers (MERRF) is a common mutation causing Mitochondrial Disease. When present it frequently runs in families with 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 and the presence of high amounts of mutated or abnormal mitochondrial DNA then 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. Since this is not inherited on the mitochondrial genome this means the pattern of inheritance of this disease only occurs if both parents carry an abnormal gene which come together to give the patient who has two bad copies of the thymidine phosphorylase gene. This is called an autosomal recessive pattern of inheritance.

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 and often then confirmed by direct measurements of the enzyme thymidine phosphorylase and possibly even finding the genetic abnormalities 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 that 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 the different sized pieces of mitochondrial DNA that are missing. The genetic problem here is often inherited, but is not due to a 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 difficulties, 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 disorders, 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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