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8.1 SUMMARY

This thesis has described clinical and molecular studies in the inherited spinocerebellar ataxias, Harding established an internationally recognised clinical classification o f the inherited ataxias in 1982 (Harding, 1982), and in so-doing enabled clinicians to make a clinical diagnosis and importandy, give a prognosis in most cases. Genetic counselling was also possible, even though none o f the causative mutations had been identified at this time, and it would be another 11 years before the first o f these genes (SCAl) was identified (Orr

et al.^ 1993). Since then, a further eight SCA genes (SCA2, SCA3, SCA6, SCA7, SCA8, SCAIO, SCAl 2 and SCAl 7) have been identified, and a further six loci (SCA4, SCA5, SC A ll, SCAl 3, SCAl 4 and SCAl 6) have been mapped.

This thesis has contributed to the clinico-genetic classification o f the hereditary ataxias. The key findings o f these studies are as foUows:

1. A novel locus (SCAll) for ADCA type III has been clearly established (chapter 4).

2. The prevalence o f mutations in two o f the SCA genes (SCA7 and SCAl2) in UK subjects with cerebellar ataxia has been assessed (chapters 6 and 7). The SCAl2 expansion has been shown to be a rare cause o f ataxia in the UK.

3. A de novo expansion in the SCA7 gene has been identified (chapter 7).

4. A family with the clinical phenotype o f ADCA type II has been shown not to have an expansion in the SCA7 gene, indicating locus heterogeneity in ADCA type II.

5. The prevalence o f the SCA8 expansion has been assessed in subjects with cerebellar ataxia and the validity of the SCA8 expansion as a cause o f cerebellar ataxia has been brought into question.

The main focus o f this thesis has been the Devon Ataxia family. Chapter 4 has described linkage o f the phenotype in this family with ADCA type III to markers on chromosome 15ql5-21.1. Haplotype reconstruction in the family assigned the SC A ll locus to the

interval D15S146-D15S161. Estimates o f the physical size o f this region gave a candidate region o f approximately 7 Mb. The phenotype in a second smaller family with ADCA type III was not linked to this region. In chapter 5, efforts to identify SCAl 1 were described; the RED method failed to identify an expanded repeat segregating with the disease, numerous STSs containing CAG repeats were analysed for heterozygosity and evidence of expansion in affected individuals, and the exons and exon-intron boundaries o f the most suitable candidate gene, MAPIA, which mapped to the region, were sequenced and mutations were excluded. Further studies aimed at the identification o f SC A ll have been outlined. It has been made clear that, in common with SCA8, SCAIO and SCAl2, the mutation in SCAl 1 may not be an expanded trinucleotide repeat coding for a

polyglutamine tract, although the similarity o f the phenotype in the SCAl 1 family to that of SCA6, and the absence o f clear anticipation, raises the possibility o f a moderately expanded repeat analogous to that of SCA6, as the causative mutation.

Chapter 6 describes mutation analysis in two of the most recently described SCA genes, SCA8 and SCAl 2. The expanded trinucleotide repeats which was linked to the disease phenotype in the original SCA8 and SCAl 2 families were analysed in families with undiagnosed cerebellar ataxia, as well as in cases o f sporadic ataxia o f unknown cause. No expansions were identified at the SCAl 2 locus, indicating that this is likely to be a rare cause o f cerebellar ataxia in the UK. To date, and in keeping with this observation, only one other family with the SCAl 2 expansion has been identified.

Expansions at the SCA8 locus were not restricted to patients with cerebellar ataxia. Five large (>100 CTA/CTG) repeats in five individuals with no family or personal history of cerebellar ataxia were identified. In two o f these individuals with 133 and 101 repeats, respectively, no evidence of neuropathological features o f cerebellar ataxia in the brains of these individuals was found. These findings, together with those o f other workers, cast doubt on the pathogenicity of this expansion. It has been argued that until a biological relationship between the expanded repeat and pathogenesis o f cerebellar ataxia can be shown, predictive diagnosis in relatives o f patients with cerebellar ataxia should be withheld.

Finally, in chapter 7, analysis o f the SCA7 mutation in 18 families with ADCA type II has provided evidence o f genetic heterogeneity in this condition, analogous to that seen in ADCA types I and III. This has not been described elsewhere; all other families with the

clinical phenotype o f ADCA type II have been shown to have an expansion at the SCA7

locus. In addition, a de novo mutation in the SCAT gene was observed in one family with

ADCA type II. It has been postulated that this mechanism accounts for the maintenance o f the prevalence o f a disease which would decline without frequent new mutations, owing to the meiotic instability o f the SCA7 expansion, and the tendency for the disease to present at progressively younger age in a given family (anticipation). This hypothesis is lent further credence from the observation of multiple founders in this and in other SCA7 studies.

8.2 CONCLUDING REMARKS

The identification o f the SCA loci has to a large extent vindicated Harding’s original classification into three broad groups based on clinical features. However, numerous

controversies have also arisen; the introduction o f the term spinocerebellar ataxia has led to

confusion given that spinal cord involvement is not a universal feature o f these disorders. Moreover, certain o f the phenotypes displayed in the families in whom a given SCA has been cloned, particularly that of SCAl2 and SCAl4, precludes their inclusion within any of Harding’s clinical categories. Most clinicians and researchers alike have, until now, used the

terms autosomal dominant cerebellar ataxia and spinocerebellar ataxia interchangeably, but this is

no longer truly appropriate. For example, the SCAl 2 phenotype, as discussed in chapter 6, is that o f a complex multisystem disorder o f which cerebellar ataxia is certainly one feature, but to include this phenotype within ADCA type I would be inappropriate. The Human Genome Nomenclature Committee should, in the view of the author, address this issue urgently such that the list of SCAs with phenotypes ever more diverse from that which most clinicians would recognise as tme autosomal dominant cerebellar ataxia does not grow uncontrollably, and bring either the clinical or the genetic classification into ‘disrepute’.

Notwithstanding these concerns, the ability to make a genetic diagnosis in an increasing number o f families with hereditary ataxia deserves much credit. It is self evident that this win lead to a much greater demand for predictive diagnosis in family members at risk o f a given SCA. Perhaps the initial sense of empowerment felt by clinicians and researchers alike which has been so prevalent over the last ten years is being partially superseded by an a degree o f cynicism and reservation as the establishment digests the moral and ethical implications o f the genetic revolution. It is understandable that many lay individuals are

unable to discriminate between what is involved in the procedure o f predictive genetic diagnosis and, for example, genetically modified food, and therefore view the whole o f the science with zealous scepticism and opposition. It is clear therefore, that it befalls all those in the scientific community, clinicians, government and perhaps most importantly the media, to explain the advances in science to the public both responsibly and clearly. It may be that this, rather than the scientific goals themselves, will be our greatest challenge.