RECENT ADVANCES IN THE GENETICS OF DYSTONIA

In the last two years, there have been a number of dramatic advances in our understanding of the genetics of dystonia. The reason for studying genes is that there is increasing evidence that there is a genetic basis for many forms of dystonia, and identification of these genes will help us understand what causes dystonic movements. Specifically, gene identification will allow more accurate genetic counselling and if necessary testing for individuals at risk of developing familial dystonia. In addition, if we understand the mechanisms behind dystonia, it may lead to novel treatments.

Thirteen different dystonia genes have now been implicated or mapped and of these, three have actually been isolated (cloned). One of the most important genes is the DYT1 gene. This causes childhood onset generalised dystonia which often starts in one limb and then spreads to involve the other arms, legs and trunk. It can be very incapacitating and it is inherited in a manner that is called autosomal dominant. This means that if you have a parent who is affected by this condition, you have 1:2 chance of inheriting the gene and developing the condition. Fortunately, this particularly form of dystonia is relatively rare, but the DYT1 gene was isolated and has been studied intensively in the last two years. We hope the study of how the normal and abnormal DYT1 gene functions will lead to a better grasp of the underlying problems in the brain leading to dystonic movements.

Every gene is the genetic blue print for a specific protein. The DYT1 gene is the code for a protein called torsin A. It is not clear what the precise role of torsin A is in normality, but it may form a ring and sit in membrane in cells and interact with other proteins to either dispose of these, or to alter/modify them.

Interestingly, torsin A is highly expressed in areas of the brain containing the chemical messenger dopamine. This supports a longstanding hypothesis that it is abnormalities in the dopamine pathways that may led to dystonic movements. Studies in rats suggests that torsin A is particularly important in early developing stages of the basal ganglia (those areas of the brain deeply involved in the control of movement). This suggests that the problems with motor pathways in the brain that lead to dystonia are laid down at an early stage of development of the brain.

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Other ways of studying brain function are to look at biochemistry within brains in post-mortem studies. There are very few brains of individuals who had DYT1 dystonia, and the limited studies suggest again that there may be an alteration in concentrations of dopamine suggesting that there is an increased turnover of dopamine within these areas of the brain.

An alternative method to analyse the function of a particular protein such as torsin A is to study it within individual cells. There have been a number of studies where both the normal human torsin A and the abnormal mutant form have been put into cells grown in culture.

In the Department of Neurosciences at the Royal Free and University College Medical School, we have used human nerve cells (SHSY5Y) which are either expressing normal human torsin A or the abnormal or mutated form. Our studies have shown that the normal protein is expressed throughout the cell, but the mutant torsin A forms inclusions or “lumps”. When one tries to analyse which particular compartment of the cell is involved, the normal protein is associated with an area of the cell called endoplasmic reticulum. This is similar to a factory, in that it is involved in producing and modifying proteins used for many cellular functions. Studies in the United States suggest that the mutant aggregates or inclusions of torsin A are also associated with the endoplasmic reticulum, but form swirls of membranes presumably disrupting their function.

Our studies in human cells, however, suggest that the lumps of abnormal protein are actually elsewhere in the cell, and may be associated with what are known as vesicles. Vesicles are little packets which contain chemical messages, and are released to allow one nerve cell to talk to another. If these vesicles or packets which we have identified function in an incorrect way because of the abnormal protein, this may alter the way that neurons communicate with each other and potentially lead to disruption of the motor pathways and dystonic movement. It is interesting to note that the vesicles we have identified may well be those which contain dopamine, again confirming the possible role of abnormal dopamine neurotransmission in dystonia.

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The majority of people with dystonia have adult onset focal dystonia where there are no obvious other family members affected. In these individuals, we still feel there may be a genetic susceptibility. One way of studying this is looking at large populations of people with dystonia and comparing normal variations in genes in these groups compared with control population. In a study we have performed looking at cohorts of people with either cervical dystonia (spasmodic torticollis) or blepharospasm, we have identified an association with the gene for a particular dopamine receptor (the D5 receptor). Our hypothesis is that a variant of this gene (and hence the receptor), may work in a slightly different way and lead to susceptibility of developing dystonia in later life. This may be because there is a later environmental insult, such as trauma and so on, which triggers dystonia in these susceptible people. It is quite possible that individuals who develop focal dystonia will have a hand full susceptibility genes which when combined with an environmental insult, leads to development of dystonia. Only other studies looking at populations of people with dystonia and controls will identify such genes.

In the last two years, researchers have been focussing on molecular mechanisms in dystonia, particularly since genes have been identified. The findings so far suggest that there is a problem with the way that dopaminergic neurons talk to other neurons within the motor pathways and this leads to dystonic movements. The development of further cell and animal models will allow these pathways to be dissected out further and, in the future, hopefully will be tools in which we can test new treatments.