Reduced Penetrance of SCA8 in Other Families

In the MN-A family, SCA8 is transmitted in an autosomal dominant pattern with reduced penetrance of alleles less than 110 combined repeats. In other families, SCA8 shows a complex inheritance pattern in which only a subset of expansion carriers from a given family is affected (Koob et al. 1999; Day et al. 2000; Ikeda et al. 2000b; Cellini et al. 2001; Topisirovic et al. 2002). Representative SCA8 pedigrees are shown in Fig. 4 (Ikeda et al. 2004). Family A appears to transmit ataxia in a dominant pattern with affected individuals in multiple generations. Family B appears recessive with multiple affected individuals in a single generation, while the affected individual in family C presents as a sporadic case with no other affected family members. In contrast to the relatively large number of affected patients in the MN-A family (n = 13), 25 of the remaining 36 ataxia families had only a single affected individual, nine families had two affected individuals, and only two families had three affected

Apparently Dominant Apparently Recessive Apparently Sporadic Unaffected A. Family C7 B. Family C8 C. Family C20 D. CEPH1416family

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25/23 228 280 228

130 800

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0001110 116118 93 85

Fig. 4 SCA8 pedigrees with varying degrees of disease penetrance. Black symbols are for individuals affected by ataxia, and unaffected expansion carriers are indicated by symbols with a dot inside them. A diagonal line through a symbol denotes an individual who is deceased. The size of the expanded SCA8 allele is shown below the individuals. (Reproduced with permission from University of Chicago Press and Ikeda et al. (2004) Am J Hum Genet 75:3-16. © 2004 by The American Society of Human Genetics. All rights reserved)

individuals. Although only a subset of the expansion carriers in the MN-A family developed ataxia (13/35), the penetrance of disease was significantly higher in the MN-A pedigree than in the 36 smaller ataxia families we have studied as well as families reported by other groups (Koob et al. 1999; Day et al. 2000; Ikeda et al. 2000b, 2004; Juvonen et al. 2000; Cellini et al. 2001; Topisirovic et al. 2002). Of note, MRI analysis of a 71-year-old patient, who was clinically unaffected, showed mild cerebellar atrophy (Ikeda et al. 2000b), indicating that asymptomatic individuals may still show signs of cerebellar atrophy in imaging studies.

In summary, the tight correlation between repeat size and pathogenesis found in the MN-A family is not found in other ataxia families that have been reported (Ikeda et al. 2004). Among the additional SCA8 families examined, repeat sizes among affected and unaffected expansion carriers overlap and often exceed the pathogenic threshold found in the MN-A family. These data demonstrate that SCA8 expansions found among ataxia patients vary dramatically in size and that the presence of an SCA8 expansion cannot be used to predict whether or not an asymptomatic individual will develop ataxia (Ranum et al. 1999; Moseley et al. 2000; Worth et al. 2000; Ikeda et al. 2004).

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