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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