The Genetic Survey of Dystonia (GSD)

As the above piece of research is eventually about to come to fruition after many different stops and starts, I thought you might all like to know something about exactly what we are trying to do. At the end of this article I will tell you what we intend to do next. However before then, I will attempt to give you all a brief outline of what we mean by the GSD and DNA. I apologise to those medical readers of this article for being too simple and probably containing some errors, but I think everyone will agree with the overall basic outline herein contained.

The GSD was started on 14th May 2003 and will end this year. We used to take a small blood sample and currently have 297 such samples stored at Newcastle University Medical School under the auspices of Professor Patrick Chinnery. This small sample is currently being analysed and we hope to have the results quite soon to find out who has what genes which might be causing their dystonia.

The important material in genes is known to be deoxyribonucleic acid or what everyone knows as DNA. The human body contains 100 trillion cells (ie one million million). Each cell contains a black blob called a nucleus and inside the nucleus are two sets of the genome. One set of the genome comes from your mother and the other set from your father. Each set contains between 60,000 and 80,000 genes and both sets are on 23 chromosomes. In practice there are often small and subtle differences between the two sets thus causing blue eyes or red hair or being left handed, etc.

lllOf these twenty three chromosomes, each one has several thousand genes. Each gene has something called exons, which are interrupted by introns. Each exon is made up of codons and each codon is made up of bases. There are over one billion codons in the human body. Each genome is written in three letter sets using only four letters. These are A = Adenine, C = Cytosine, G = Guanine and T = Thymine. These are "written" on long chains of sugar and phosphate called DNA molecules. Each chromosome is one pair of (very) long DNA molecules. Let us now examine which DNA molecules are thought to cause dystonia in all its various forms. May I here again apologise to the medical profession as some of the following has since been updated, but here is my current version taken from the Dystonia Europe conference in Hamburg, Germany during October 2008.

There are thought to be just five known genes which cause different forms of dystonia. Each dystonia gene is given a number, such DYSTONIA No 1, ie DYT1. Everyone has heard of the DYT1 gene, which causes early onset generalised torsion dystonia and is found on 9q34 Torsion A. DYT3 causes Lubag Disease and is found on Xq13.1 and DYT5 which causes Dopa Responsive Dystonia (DRD) is found on 14q22 GCH 1. DYT11 is known for causing Myoclonic Dystonia and is found on 7q21 Sarcogycan. Finally there is the gene discovered by Professor Patrick Chinnery and his team at the Medical School Newcastle University known as FTL or the neuroferrintinopathy gene on 19q13. This has not yet been officially recognised but has been found in a very large dystonic family in Cumbria.

There are a number of other genes which have yet to be completely defined, but which are described below. DYT2 found in Spanish Gypsies which causes autosomal recessive torsion dystonia, DYT4 known as Whispering Dysphonia, DYT6 found in the Mennonites on n8q21-p22, DYT7 found in a German family and thought to be 18p causing adult cervical dystonia, DYT8 is a gene known to cause paroxysmal non-kinesogenic dystonia and is thought to be found somewhere around 2q33-q35, DYT9 causes choreoathetosis with episodic ataxia and spasticity on 1p21 and DYT10 also causes paroxysmal kinesogenic choreoathetosis somewhere near 16q11.2-q12.1. DYT12 causes rapid-onset dystonia - parkinsonism and is thought to be on 19q, DYT13 causes cranio-cervical-brachial dystonia (ie multi-focal / segmental dystonia) and is thought to be on 1p36.13-36.32 and DYT14 is another type of Dopa Responsive gene on 14q13. DYT15 is another gene thought to cause myoclonus / dystonia and is on 18p and finally DYT16 is an early-onset generalised dystonia on 2q with a PRKRA gene mutation.

Having given you all an oversight on the genetic nature of dystonia, I must warn you all not to get too enthusiastic. Just because DYT5 causes Dopa Responsive Dystonia (DRD) and is found on 14q22 GCH 1, for example, not everyone with DRD has this particular gene. Not everyone with Myoclonic Dystonia has the DYT11 gene which is found on 7q21 Sarcogycan. It is very important that you do not think that because of all this research being conducted around the world that a cure is just around the corner.

I usually finish my lectures by saying that dystonia is a significant movement disorder that has previously been unrecognised as such. Genetics will give us significant results, but this is only one of the ways in which we will eventually discover the cure. We are just at the beginning of a very long road and genetics is not the only way we should go. Publicity to the general public and education of the medical profession is another important aspect.

Recent advances in medical science now means that your DNA can be tested without the need for a blood test. Professor Chinnery and I have been exploring how we can take your DNA without the need for a phlebotomist (blood taker). We have discovered a company in Canada who can supply us with enough small kits that we can send them out to you in the post. You then need to fill the special tube with your spittle / phlegm and after sealing the tube post it back to us. Because the medical ethical committee which gave us permission to do this research in the first place insists that your DNA remains confidential, then each tube will just have a number written on it for my use only.

Many different organisations throughout the world test their patients for one of the known dystonia genes, but we are attempting something quite different and indeed unique. We intend to take a DNA sample from every person in the ESD who is willing to give us the sample and then store it. We will then be in a position to make a grant application to raise the £100,000 required to analyse all these samples. This will give us a tremendous advantage in research terms and will, we hope, advance the world's understanding of what causes dystonia in a diverse group of people.

Finally I come to the problem that ADDER has in completing this part of the research programme. As you know from previous articles and correspondence, none of the researchers on this project get paid anything for doing this work. This has been the case since the very beginning in 1993. This keeps our costs down considerably but the actual price of the kits has to be met somehow. Each kit will cost us about £12.00 to buy and then with postage, etc it has been estimated that each sample will cost ADDER about £15.00 to send out and receive back.

There are 2,176 people currently in the Epidemiological Survey of Dystonia (ESD). 13 are non-dystonics used as controls, 213 have died during the research period, 195 have indicated they want "no contact" with the researchers, 101 people have not completed all the research protocols and consequently I have no idea how they will react to the requests and 19 people have moved with no new address available. This means there are potentially 1,635 people available but 297 have already given us a sample of their blood. There are currently 1,338 people who are potentially available to have their DNA tested. Assuming 95% (based on our previous experience) say "Yes, I would be prepared to participate", this means that the cost to ADDER would be 1,271 x £15.00 = £19,065. Ipsen (the makers of Dysport, the British botulinum toxin) have kindly agreed to donate £5,000 towards this research. We have just over £4,400 left over (February 2010) from the money awarded to us by Allergan (the makers of Botox, the American version) to complete the ESD, but this still leaves us with an almost £10,000 deficit to cover all the people in the ESD.

This is where, dear readers, we are asking for your help and participation. For those of you who can afford it, we are asking you to donate £15.00 specifically to have your DNA taken and stored for future research. I will be writing to you individually over the next few weeks asking if you would be prepared to take part in this important piece of research and furthermore asking you if you would be prepared to donate £15.00 towards the cost of your DNA being taken and stored.

There is no need to send us any money yet, but some indication as to how you feel about this suggestion would be appreciated. You can call us on 0191.477.7700 on the office telephone and if no one is there the call gets transferred to our home where Verona or I would be able to take your call.

Thank you for taking the time to read this article and I will be contacting you personally very shortly.

Dr Butler

A.D.D.E.R. Committee member and Epidemiologist