Worth, Paul Francis; (2002) Spinocerebellar ataxia: A clinical and molecular genetic study. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is concerned with the molecular genetic basis of the spinocerebellar ataxias (SCA). An introductory chapter outlining the clinical and genetic classification and pathophysiology of the spinocerebellar ataxias, is followed by further chapters as follows: 1. Spinocerebellar ataxia type 11. (Chapters 3-5). A British family was identified in which affected individuals exhibit a relatively "pure" cerebellar syndrome. Using a genome-wide searching strategy, the disease phenotype was linked to the marker D15S1028. Construction of haplotypes defined a critical region of 5cM, thereby assigning the SCA11 locus to the proximal long arm of chromosome 15. Analysis of Genemap '99 has resulted in a list of approximately 154 non-redundant ESTs and known genes that are potential candidates for SCA11, The exons and exon-intron boundaries of one of the microtubule- associated protein genes, MAP1A, have been sequenced and no mutations were identified. 2. Spinocerebellar ataxia type 8 and type 12. (Chapter 6). Patients with cerebellar ataxia have been screened for the presence of the recently-identified SCA8 and SCA12 trinucleotide repeat expansions; expanded SCA8 alleles were identified in 2 families. However, expansions of 133 and 174 were also detected in 2 control individuals, and repeats of ≥ 100 in a further 3 subjects were found; two of these had unrelated neurological conditions. No expansions in SCA12 were identified in either control or ataxia patients. These results suggest that SCA12 is a rare cause of cerebellar ataxia and question the validity of SCA8 as a causative gene for cerebellar ataxia. 3. Spinocerebellar ataxia type 7. (Chapter 7). The SCA7 mutation was found in 47 patients and 7 at risk subjects from 17 ADCA II families. In one case, a de novo mutation was identified. One family with the clinical phenotype of ADCA type II did not have the CAG expansion indicating locus heterogeneity. Repeat sizes in normal chromosomes fell into two distinct ranges, 7-19 CAG repeats and 28-35 repeats. The range of repeat size of pathological alleles was from 37 to ~220. The repeat size showed significant negative correlation with both age at onset and death. Subjects with smaller repeats tended to have a less complicated neurological phenotype and a longer disease duration while the converse applied to subjects with larger repeats.

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