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30 - Spinocerebellar ataxia type 5
- from PART VIII - DOMINANTLY INHERITED PROGRESSIVE ATAXIAS
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- By Christina L. Liquori, Department of Genetics, Cell Biology, and Development, Lawrence J. Schut, Department of Neurology, CentraCare Clinic, St Cloud, Minnesota, USA, H. Brent Clark, Department of Laboratory Medicine/Pathology, John W. Day, Department of Neurology, Institute of Human Genetics, University of Minnesota, USA, Laura P.W. Ranum, Department of Genetics, Cell Biology, and Development
- Edited by Mario-Ubaldo Manto, University of Brussels, Massimo Pandolfo, Université de Montréal
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- Book:
- The Cerebellum and its Disorders
- Published online:
- 06 July 2010
- Print publication:
- 15 November 2001, pp 445-450
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Summary
Introduction
A ten-generation family with a clinically mild autosomal dominant form of spinocerebellar ataxia (SCA) was identified in 1992 (Ranum et al., 1994). This Caucasian kindred has two major branches that both trace their ancestries to the paternal grandparents of President Lincoln (Fig. 30.1). Abbreviated versions of the two branches of the family are shown in Fig. 30.2. DNA has been obtained from 215 members (60 affected) of this kindred. After excluding linkage to the known ataxia loci, a genome wide screen mapped the disease locus, spinocerebellar ataxia type 5 (SCA5), to chromosome 11q13 (Ranum et al., 1994). Although disease onset is typically in the third or fourth decade, it can range from 10 to 68 years. Signs and symptoms progress over several decades, beginning with a mild disturbance of gait, incoordination of upper extremities, and slurred speech.
SCA5 primarily affects the cerebellum and is clinically more benign (Ranum et al., 1994) than other SCAs (Gouw et al., 1994; Yagishita and Iouue, 1997). In general, the adult-onset cases appear similar to patients with SCA6 (Zhuchenko et al., 1997) and to previously described families with relatively ‘pure’ forms of cerebellar ataxia (Holmes, 1907; Harding, 1983). Whereas adult-onset SCA5 is disabling, the most striking clinical distinctions from SCA1, SCA2, SCA3, SCA4, and SCA7 are that SCA5 progresses more slowly and generally does not shorten life (Ranum et al., 1994). This clinical difference is probably due to the lack of bulbar paralysis in all of the adult-onset SCA5 patients examined. Bulbar paralysis in other forms of dominant ataxia often leads to a weakened ability to combat recurrent pneumonia (Zoghbi, 1991).
33 - Spinocerebellar ataxia type 8
- from PART VIII - DOMINANTLY INHERITED PROGRESSIVE ATAXIAS
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- By Melinda L. Moseley, Department of Genetics, Cell Biology, and Development, Institute of Human Genetics, University of innesota, Minneapolis, USA, Lawrence J. Schut, Department of Neurology, Institute of Human Genetics, John W. Day, Department of Neurology, CentraCare Clinic, St Cloud, Minnesota, USA, Laura P.W. Ranum, Department of Genetics, Cell Biology, and Development, Institute of Human Genetics, University of innesota, Minneapolis, USA
- Edited by Mario-Ubaldo Manto, University of Brussels, Massimo Pandolfo, Université de Montréal
-
- Book:
- The Cerebellum and its Disorders
- Published online:
- 06 July 2010
- Print publication:
- 15 November 2001, pp 469-480
-
- Chapter
- Export citation
-
Summary
Introduction
It was recently demonstrated that an untranslated CTG expansion causes a novel form of ataxia – spinocerebellar ataxia type 8 (SCA8: Koob et al., 1999a). In addition to being the first example of a dominant SCA that is not caused by the expansion of a CAG repeat translated into a polyglutamine tract, the mutation underlying SCA8 shows marked intergenerational changes that are probably responsible for dramatically variable disease penetrance. The RAPID cloning method used to isolate the SCA8 CTG expansion and the clinical and genetic features of the disease are discussed below.
RAPID cloning
As part of a broader goal to understand better the various genetic causes of ataxia and to develop a resource to clone novel ataxia genes, an ataxia DNA collection has been established that now represents over 380 different ataxia kindreds with dominant, recessive, and sporadic forms of adult-onset ataxia (Moseley et al., 1998). Table 33.1 summarizes the inheritance patterns of the various families represented in the collection. Although direct gene tests are now available for eight of the ataxia loci, a large portion of the dominant ataxia families in our collection (∼35%) do not harbor expansions at the known loci, and thus remain genetically undefined.
To determine whether or not CAG repeat expansions are the pathogenic mechanism involved for some of these genetically undefined forms of ataxia, the repeat expansion detection (RED) assay was performed on affected family representatives. The RED assay, developed by Schalling et al. (1993), is an elegant technique that allows for the detection of potentially pathogenic trinucleotide repeat expansions without prior knowledge of chromosomal location.
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