Inheritance of Mitochondrial Diseases

The main function of mitochondria is to generate ATP. The machinery to do this is called the mitochondrial respiratory chain and consists of a series of protein molecules that convert food energy into ATP. These proteins are encoded in DNA contained within each cell. Mitochondria are unique in that they have their own DNA (mitochondrial DNA or mtDNA), which codes for some of the proteins in the respiratory chain. The rest of the proteins in the respiratory chain and all of the ones needed to repair mtDNA are coded for in the cell nucleus. This means that defects in the mitochondria can be caused by either mitochondrial or nuclear DNA mutations.

 

Mitochondrial Bottleneck
Eggs are formed from precursor cells in the mothers’ ovaries. In a mother carrying a heteroplasmic mtDNA mutation there will be a percentage of normal and abnormal mitochondria throughout her body, including in these precursor cells (figure). The exact proportion will vary slightly between cells, but let’s say overall there is a 50:50 mix in the mother. Only a small fraction of the mitochondria present in the precursor cell survive in the egg. Let’s say for example that only ten survive, and by chance eight of these contain abnormal mtDNA. If that egg is fertilised, this high proportion of abnormal mitochondria will be passed on to the child. In this case, the child will be more severely affected than the mother. On the other hand, only one of the ten surviving mitochondria in another egg may be affected, in which case the child will be very mildly affected. We do not understand what controls the proportion of normal vs abnormal mtDNA in the egg and all of this means that it is very difficult to predict how a child will be affected, even if we know precisely what proportion of abnormal mtDNA the mother has.

 

Maternal Inheritance
The way that mitochondria are passed on is also unique; both the egg and sperm contain mitochondria, but following fertilization of the egg, the mitochondria from the sperm are destroyed (figure). This means that only the mother’s mitochondrial DNA is passed on to the next generation. So even if a man has a mutation in his mitochondrial DNA, it will not be passed on. In contrast, a woman with a mutation can pass it on to all of her children. Things are further complicated by the fact that although there is only one nucleus per cell containing one set of nuclear DNA, cells contain hundreds of mitochondria, and each mitochondrion contains several copies of mitochondrial DNA. We therefore have several factors to consider in thinking about inheritance.

 

Single deletion/rearrangements
Let’s start with the simplest case – a single deletion. This means that part of the mitochondrial DNA molecule is missing. This arises in the one of the mitochondria in one of the mothers’ eggs. If this egg is fertilised, then the mutation will be present in the child (boy or girl). How the child is affected depends on how much of the abnormal mtDNA it has in each tissue. As the fertilised egg divides, the mitochondria in the cells also divide and so the numbers of both normal and abnormal mtDNA molecules increases. As the embryo continues to develop, different cells are formed which go on to make all the different tissues in the body. If for example the cells that form the eye muscles have a particularly high proportion of abnormal mtDNA then those cells may not be able to make enough ATP, leading to symptoms.

Because the initial mutation arose in just one of the mothers’ eggs, the chance of her other eggs being affected is small. This is turn means that the chance of her having a second affected child is also small. Similarly, if the affected child is a girl, the chance of her eggs containing a significant proportion of abnormal mtDNA is low, and so usually her children will not be affected. So, single deletions arise afresh in an affected individual and there is only about a 5% chance of it being maternally inherited.

Point mutations
Next, let’s consider a point mutation, for example the MELAS or MERRF mutation. Either some of the patients’ mtDNA is affected (heteroplasmy) or in some cases all of it is (homoplasmy). In female patients, the mitochondria in the ovaries are also affected which means that the mutation can be passed on to all of her children. How severely they are affected depends partly on how many abnormal mitochondria the egg contains. Male patients cannot pass on the mutation, because although their sperm cells contain affected mitochondria these do not survive in the embryo. Most but not all, point mutations are therefore inherited and are passed on down the female line (“maternal inheritance”), so several members of a family can be affected.

Nuclear gene mutations
The last case to consider is that of a nuclear gene defect, an example of which would be a mutation occurring in a gene encoding one of the mtDNA repair enzymes (proteins). Throughout life mtDNA develops random deletions of parts of the molecule, and normally these are rapidly repaired. In a mutation of the nuclear-encoded repair proteins this does not happen and the number of deletions builds up, eventually damaging the mitochondria. Because the genes are carried in the nuclear DNA, they are passed on like any standard genetic disease (figure). That is, if one abnormal copy of the gene is enough to cause problems then inheriting one abnormal gene from either parent will cause disease ie a fifty-fifty chance of inheritance. If on the other hand both copies of the gene must be missing to cause disease then this will only happen in the rare occasion that two carriers (each missing one copy) meet and have children. The risk to their children is one in four of being affected, with half becoming carriers and one in four escaping completely. In the first case this is called autosomal dominant inheritance, and in the latter it is autosomal recessive. Only some of the nuclear genes that cause mtDNA deletions are known, but it is important to try and identify them as we can then better predict the risk to other family members.

It is very important to remember that the details given here are only general principles. Advice regarding the risks for individual patients of inheriting or transmitting the disease must be given by a specialist.

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