Anticipation and integracional repeat instability of spinocerebellar ataxia type 17 (SCA17)
Rasmussen, Astrid1,2; De Biase, Irene1; Alonso, Elisa2; Bidichandani, Sanjay1. 1University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 2Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez, Mexico City, D.F., Mexico.

Background: SCA17 is caused by the expansion of a CAG/CAA trinucleotide repeat in the TBP gene. Most pathogenic alleles are stably transmitted from parent to offspring with no resulting anticipation. This is because of the interrupted and complex nature of the repeat tract.

Objectives: To analyze the repeat configuration, intergenerational instability and anticipation in seventeen additional patients from three large SCA17 families with expansion of “uninterrupted” alleles.

Methods: PCR and direct sequencing was carried out to identify the length and repeat configuration of the CAG/CAA alleles in the TBP gene. We analyzed five intergenerational transmissions in our cohort and compared them to the five previously reported to characterize anticipation and intergenerational instability.

Results: All our newly identified SCA17 patients carried the infrequent uninterrupted allele, which contributes to <10% of the reported expanded alleles. The size of the repeat had a very strong correlation with age of onset (R = -0.93; P < 10-9), and the repeat had a clear tendency to expand during transmission (9 of 10 cases). Anticipation correlated with parental age (R = 0.75; P = 0.007), with greater anticipation occurring via paternal transmission (P = 0.009). The contribution of each repeat to number of years of anticipation (mean = 5.7 years / triplet gained) is higher than for any other CAG repeat disease, possibly because of the vast number of genes that TATA-binding protein interacts with. Importantly, seven of our 17 patients (41%) had an age of onset before 21 years, and at least one affected child was present in each pedigree. It is therefore necessary to consider SCA17 in the differential diagnosis of pediatric patients with ataxia.

Conclusions: Our data indicate that intergenerational transmission of the uninterrupted pathogenic alleles in SCA17 almost always result in further expansion and genetic anticipation. Previously inconclusive observations regarding genetic anticipation in SCA17 were most likely due to the lack of distinction between interrupted and uninterrupted alleles. It is recommended that SCA17 alleles be sequenced for adequate patient management and genetic counseling. Moreover, SCA17 needs to be considered in the differential diagnosis of ataxia in children.