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 Centre for Mitochondrial Research website. 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 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. For people living in the UK, reproductive advice can be discussed with the doctors at any of the 3 highly specialised mitochondrial disease centres in Newcastle, London and Oxford.

One reproductive 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 grown in the 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)

It is important that mitochondrial DNA (mtDNA) is correctly maintained to allow the mitochondria to function. Problems with mtDNA maintenance can reduce the amount and quality of the mtDNA, which can lead to impaired energy production. This can cause a particular type of mitochondrial disease known as 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.

Who does MDDS affect?

Mitochondrial DNA depletion syndromes can affect both children and adults. The early-onset form affecting infants and children is most severe and often fatal in early life. The late-onset form that affects adults is less severe and disease progression is often slower.

How many people does MDDS affect?

Mitochondrial DNA depletion syndromes are extremely rare. For example, there are thought to be <100 cases of mitochondrial DNA depletion syndrome associated with the TK2 mutation throughout the world. The prevalence is even lower for mitochondrial DNA depletion syndromes associated with mutations in other genes.

What are the clinical features of MDDS?

Mitochondrial DNA depletion syndromes are associated with many clinical features, some of which can be fatal in childhood. The type and severity of symptoms will often depend on the particular gene that is affected. In some cases, the main clinical feature is progressive muscle weakness, which can make breathing difficult and lead to respiratory failure. The other cases the brain may be affected causing seizures, stroke-like episodes, movement disorders or developmental delay. Other parts of the body commonly affected include the liver, kidney and gastrointestinal tract and hearing loss is also a feature of some gene mutations.

What are the causes of MDDS?

Mitochondrial DNA depletion syndromes are caused by genetic errors (mutations) in genes found within the nuclear DNA. These mutations affect genes that have an essential role in the replication and maintenance of mtDNA.

Genes known to be associated with MDDS disease include TK2, POLG, RRM2B, SUCLA2, SUCLG1, DGOUK, MPV17, TYMP and C10orf2.

How is MDDS inherited?

In order to develop a Mitochondrial DNA depletion syndrome you need to have two copies of the faulty gene. 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 gene, which is sufficient to maintain health. This inheritance is known as autosomal recessive and 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).

It is also possible for a gene to spontaneously mutate, which if combined with one parent passing on a faulty gene, may also cause disease.

Are there any treatments for MDDS?

Treatment usually focuses on managing the symptoms and providing supportive care. There is an experimental treatment in development that may benefit some patients with mitochondrial DNA depletion syndrome. This is known as nucleoside bypass therapy.

What is nucleoside bypass therapy?

There are four chemical ‘building blocks’ needed to maintain mtDNA, collectively known as deoxynucleoside triphosphates (dNTPs). If the body is unable to produce these dNTPs due to a mutation in one of the many genes that are needed to make them, this can result in mitochondrial DNA depletion syndrome. It may be possible to ‘bypass’ this shortage of dNTPs by providing deoxynucleosides, or similar building blocks known as deoxynucleotides, to some patients with mitochondrial DNA depletion syndrome as an oral medication. This may restore the supply of dNTPs required for mtDNA maintenance, which could improve some of the clinical symptoms associated with the condition.

Is nucleoside bypass therapy being used?

Based on preclinical research, nucleoside bypass therapy is being used for a small number of patients in both Europe and America on compassionate grounds. These patients have mitochondrial DNA depletion syndrome associated with the TK2 mutation, which mainly affects muscle.

Will nucleoside bypass therapy be suitable for all mitochondrial DNA depletion syndromes?

It is unclear at this stage whether nucleoside bypass therapy could be used for mitochondrial DNA depletion syndromes caused by mutations in genes other than TK2. Further preclinical studies are required to determine whether the therapy can be used to treat all mitochondrial DNA depletion syndromes.

Can MDDS 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 MDDS occurring.

However, once a genetic mistake has been identified, there are reproductive options that can be offered to prevent MDDS in the next pregnancy. For people living in the UK, reproductive advice can be discussed with the doctors at any of the 3 highly specialised mitochondrial disease centres in Newcastle, London and Oxford.

One reproductive 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 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.

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

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Leigh syndrome

Leigh syndrome (also known as Leigh disease) is a mitochondrial disease that usually affects young children. It is a severe neurological condition that typically affects development of movement, posture and mental abilities, with children sometimes losing these skills after a period of what appeared to be normal development. Leigh syndrome is caused by a number of different genetic mistakes (mutations) found in either the nuclear or mitochondrial DNA and so can be inherited in many different ways.

Who does it affect?

Leigh syndrome affects approximately 1 in 40,000 newborns, with symptoms usually starting in the first year of life. Though extremely rare, some people may not develop symptoms until early adult life, while others may have symptoms that develop more slowly in childhood.

What are the clinical features?

Children with Leigh syndrome are often weak and floppy, but this may not be obvious until they are several months old. Swallowing, breathing, movement and posture maybe particularly affected as the disorder involves parts of the brain responsible for these functions. Most children with this condition will gain developmental skills, such as rolling or sitting independently, only to lose them again. This is called developmental regression and typically occurs at times when children with Leigh syndrome are unwell with minor childhood illnesses such as ‘tummy bugs’ or ‘coughs and colds.’ This regression may be the first indication of the underlying mitochondrial problem, but other features such as recurrent vomiting and poor weight gain are often present. Following recovery from the illness, there may be recovery of some of the skills lost. Children with Leigh syndrome may deteriorate in this way over many years, or they may follow a more rapidly progressive decline over a period of months.

How is it diagnosed?

Specific patterns of brain involvement on an MRI scan along with typical clinical findings usually suggest the diagnosis. Lumbar puncture (a procedure used to collect a sample of spinal fluid) may also be helpful in confirming a disorder of mitochondrial function (raised cerebrospinal fluid lactate) and excluding other medical problems. Although less frequently performed now, muscle biopsy is often helpful in confirming that mitochondrial function is abnormal and may help direct more specific genetic testing.

What causes Leigh syndrome?

Leigh syndrome can be caused by genetic variations in over 75 different genes. These include nuclear genes (within the nuclear DNA) or mitochondrial genes (within the mitochondrial DNA).

All of the mutations disrupt the process of energy production by the mitochondria. One of the main jobs of mitochondria is to convert energy in food (carbohydrates and fats) into a form that can be used by the cell. There are five protein complexes (named complex I to complex V) that make up the energy chain needed for this process of energy conversion. Many of the genetic variations causing Leigh syndrome affect the proteins that make up these complexes or how they are put together.

What genes are associated with Leigh syndrome?

The most common genetic variants causing Leigh syndrome are found in genes needed to make complex I. These variations can occur in either the nuclear or mitochondrial DNA. Other variations in the genes needed to make complex IV and complex V are also common causes of Leigh syndrome. Sometimes the genetic variant will cause a fault that results in more than one complex being affected.

Some genetic variants causing Leigh syndrome disrupt other processes related to energy production. For example, Leigh syndrome can be caused by variants in genes that make the pyruvate dehydrogenase complex or coenzyme Q10. Variations in genes that are involved in making or repairing mtDNA can also affect energy production by the mitochondria and cause Leigh syndrome. Mitochondria have to bring in or ‘import’ lots of proteins that are essential for energy conversion. Variants in genes responsible for the import machinery can also cause Leigh syndrome.

Some examples of nuclear genes associated with Leigh syndrome include:

AIFM1 / BCS1L / BTD / C12orf65 / COX10 / COX15 / DLAT / DLD / EARS2 / ECHS1 / ETHE1 / FARS2 / FBXL4 / FOXRED1 / GFM1 / GFM2 / GTPBP3 / / HIBCH / IARS2 / LIAS / LIPT1 / LRPPRC / MTFMT / NARS2 / NDUFA1 / NDUFA2 / NDUFA4 / NDUFA9 / NDUFA10 / NDUFA11 / NDUFA12 / NDUFAF2 / NDUFAF5 / NDUFAF6 / NDUFS1 / NDUFS2 / NDUFS3 / NDUFS4 / NDUFS7 / NDUFS8 / NDUFV1 / NDUFV2 / PDHA1 / PDHB / PDHX / PDSS2 / PET100 / PNPT1 / POLG / SCO2 / SDHA / SDHAF1 / SERAC1 / SLC19A3 / SLC25A19 / SUCLA2 / SUCLG1 / SURF1 / TACO1 / TPK1 / TRMU / TSFM / TTC19 / UQCRQ

Some examples of mitochondrial genes associated with Leigh syndrome include:

MT-ATP6 / MT-CO3 / MT-ND1 / MT-ND2 / MT-ND3 / MT-ND4 / MT-ND5 / MTND6 / MT-TI / MT-TK / MT-TL1 / MT-TV / MT-TW

How is Leigh syndrome inherited?

Leigh syndrome can be inherited in many different ways depending on which gene contains the variant that is causing the condition. It is most commonly inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the faulty gene to develop the condition. Typically, both parents carry one copy of the faulty gene but do not show signs or symptoms of the condition themselves. 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). This pattern of inheritance is seen for most of the nuclear genes associated with Leigh syndrome.

Leigh syndrome can also be inherited in a maternal pattern when the variant is found in a mitochondrial gene (within the mitochondrial DNA). This happens because only mothers who carry a faulty mitochondrial gene can pass this onto their children. Fathers who carry a faulty mitochondrial gene cannot pass this on. This means that both male and female children can be affected by the condition but only daughters can pass the faulty mitochondrial gene onto their own children. It is not possible to determine how many copies of the faulty mitochondrial gene will be passed from a mother to her children, however, which makes it very difficult to predict the extent to which her children will be affected by the condition. This is known as the ‘genetic bottleneck’ and can make genetic counselling challenging.

In a small number of cases, Leigh syndrome can be inherited in an X-linked recessive pattern when the variant is found in a nuclear gene located on the X chromosome (which is one of the two sex chromosomes). Because males carry only one X chromosome, one copy of the faulty gene is enough to develop the condition. In females who carry two X chromosomes, both copies of the gene must be faulty to develop the condition. This means that males are affected by X-linked recessive disorders more frequently than females. Fathers cannot pass X-linked recessive disorders to their sons.

Can Leigh syndrome be treated?

There is no specific treatment for Leigh syndrome.

Can Leigh syndrome be prevented?

If the genetic variant is present either in the nuclear or mitochondrial DNA then there is nothing that can be taken during pregnancy or given to the infant that will prevent Leigh syndrome occurring.

However, once a genetic variant that causes Leigh syndrome has been identified in either the nuclear or mitochondrial DNA, there are a number of reproductive options that can be offered in the next pregnancy. For people living in the UK, reproductive advice can be discussed with the doctors at any of the 3 highly specialised mitochondrial disease centres in Newcastle, London and Oxford. Referral to a specialised Mitochondrial Reproductive Advice Clinic in Newcastle is possible for those women with mitochondrial DNA variants.

One reproductive option is prenatal testing which involves testing cells from the baby in early 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 chorionic villus biopsy. The faulty gene is examined in this biopsy to see which copies have been inherited. If faulty copies of the gene have been inherited (with consideration given to the number of faulty copies if the mutation is in the mitochondrial DNA) then termination of the pregnancy is offered.

Preimplantation genetic diagnosis (PGD) is another reproductive option that can be offered once a genetic diagnosis has been made. This requires that the parents go through an IVF cycle to generate a number of early embryos that can be tested in the lab to determine if the faulty gene has been inherited (or the number of faulty copies if the mutation is in mitochondrial DNA). Only embryos that do not carry the faulty gene (or carry the faulty gene at low levels if the mutation is in the mitochondrial DNA) will be selected for transfer to the womb. It is important to note, however, that PGD may fail to identify any suitable embryos for transfer and even if an embryo is transferred to the womb, it may not result in a pregnancy.

If PGD is unsuitable for a woman who carries a genetic variant in her mitochondrial DNA, another reproductive option is mitochondrial donation. This is a new IVF-based treatment that can prevent a mitochondrial DNA variant being passed from a mother to her child. It involves using a donor egg with healthy mitochondrial DNA which is combined with the nuclear DNA from both parents, resulting in a child with a reduced risk of mitochondrial disease. There is only one centre in Newcastle that is currently licensed to perform mitochondrial donation and every patient wishing to use mitochondrial donation will also need regulatory approval.

 

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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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