One of the most significant genetic advances in recent years has been reported for Huntington`s Disease (HD). This is a progressive autosomal dominant neurodegenerative disorder, with psychiatric symptoms and chorea being its main features. The birth frequency of heterozygotes is about 1 in 3000, so that 1 in 1500 of the population will be at 1 in 2 risk. The mean age of onset of HD is 49 years but the range is 2 to 90 years. When onset is in childhood, inheritance is usually from an affected father. New mutations occasionally occur for HD, but none have been described for childhood onset cases. The gene was located to the short arm of chromosome 4 ten years ago (Gusella et al 1983) and soon after this it became possible in some families to predict which relatives had inherited the HD gene by following the inheritance of closely linked DNA markers. However groups throughout the world, including the UK HD consortium, have stressed the importance of careful counselling before applying the predictive test, and of adequate support afterwards (Harper & Morris 1991).
On March 24th 1993, the International HD Collaborative Research Group announced the identification and sequencing of the HD gene (MacDonald et al 1993). The gene codes for a 348K protein (now called huntingtin) which has no homology with a previously described protein. This was one unusual finding; the second was that there is a trinucleotide repeat within the gene whose size correlates with the presence or absence of disease. (This had been predicted by a few people including John Timson, writing in the March issue of the Galton Institute Newsletter). Thus, in the 75 families studied by MacDonald et al, a range of 11 to 35 copies of (CAG) was found on normal chromosomes and a range of 42 to 100 copies on HD chromosomes. The largest numbers of repeats were found in the few patients with juvenile onset, and these had increased in size from the transmitting parent. Two healthy parents, with offspring considered to be new mutations, had (CAG) repeats of 36 and 33.
These findings are both exciting and alarming. The most important implication is that the identification of a novel protein will lead to investigations into its normal function, into the fault that occurs in HD, and to ways of modifying that fault. It is interesting that HD is not caused by the lack of normal activity of the mutant gene, but by its altered function, or by the accumulation of an abnormal product. This conclusion arises because the mRNA of huntingtin was present in five homozygotes for HD and because patients with chromosomal deletions encompassing the gene do not develop HD.
The second implication is that asymptomatic gene carriers may be recognised by a simple search for an increased number of repeats without recourse to studying DNA from the rest of the family. However some mutations causing HD may turn out to be due to a different mechanism, unaccompanied by an expanded trinucleotide repeat. Such a phenomenon probably means that the risk of a false negative presymptomatic test is about 1 per cent. This simple ability to perform presymptomatic tests is likely to lead to a great demand from relatives at high risk. They will wish to know their genetic status in order to decide how to plan their numbers of children, how to manage businesses or plan careers, how best to provide for their families in the future, or what to tell their adult offspring who may themselves be embarking on parenthood. The test will give great relief from anxiety in over one half, but will cause distress and depression in some of those given bad news. A few given bad news may suffer very severe psychiatric problems amd may consider suicide. Therefore careful and thoughtful counselling has to be given before the test, as well as support afterwards. The expected work load of Clinical Genetics Units may increase by as much as 30%.
Presymptomatic testing will lead to a dramatic fall of HD, for relatives who come to genetic clinics consider HD to be sufficiently serious to warrant family limitation. If those identified as gene carriers decide to have no children, or to have prenatal diagnosis with termination of affected pregnancies, then the birth frequency of HD heterozygotes could fall by one half within 1 or 2 generations.
Finally, presymptomatic testing will bring to light various ethical and social problems, on a scale not hitherto encountered in clinical genetics. For example, what will be the effect on his/her healthy parents if the 20-year-old grandchild of an HD sufferer requests presymptomatic testing and is found to be positive? Are there ever reasons for another party being told the results of an individual`s test? An insurance company, for example, or the police in the course of a criminal investigation, or the spouse who wants custody of the children following a divorce? These and other issues will have to be dealt with, while scientists explore the function of huntingtin. There is no doubt that the story will be fascinating, and one that, on balance, will benefit HD families.
Sarah Bundey
References
Gusella J F et al. A polymorphic DNA marker genetically linked to Huntington`s Disease. Nature 1983; 306: 234-238
MacDonald M E et al (for the Huntington`s Disease Collaborative Research Group). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington`s Disease chromosomes. Cell 1993; 72: 971-983
Harper P S, Morris M J. Family Screening for Genetic Disorders - lessons from Huntington's Disease. In: Roberts D F, Chester R (Eds). Molecular Genetics in Medicine. Macmillan Press (in association with The Galton Institute). 1991; 145-160.