Clinical features and ATTCT repeat expansion in spinocerebellar ataxia type 10

Abstract

Background: Spinocerebellar ataxia type 10, an autosomal dominant disease characterized by ataxia and seizures, is caused by a large expansion of an unstable ATTCT pentanucleotide repeat.

Objectives: To characterize the phenotypic expression of spinocerebellar ataxia type 10 and to examine the genotype-phenotype correlations in 2 large families.

Design: Clinical characterization and genotype-phenotype correlation.

Setting: Studies at 2 medical schools with private practice referral.

Patients: Twenty-two affected individuals from 2 large Mexican American pedigrees.

Results: Of the 22 individuals, ataxia was the initial symptom in 21; seizure disorders developed in 11, mostly within several years following the onset of ataxia. The seizure frequency was different in the 2 families: 3 (25%) of 12 had seizures in family 1, and 8 (80%) of 10 had seizures in family 2 (P =.01). A brain magnetic resonance imaging or computed tomographic scan showed cerebellar atrophy in all patients examined. An electroencephalogram demonstrated epileptiform discharges in 4 of 8 patients studied. Although anticipation was apparent in both families, only family 1 showed a strong inverse correlation between age of onset and repeat number (r(2) = 0.79, P =.001). In family 1, 8 transmissions, of which 7 were paternal, resulted in an average gain of 1940 repeats. In contrast, despite anticipation, 2 affected male subjects transmitted their expanded alleles to 8 progenies, with an average loss of 755 repeats, in family 2.

Conclusions: Seizure is an integral part of the spinocerebellar ataxia type 10 phenotype, with documented morbidity and mortality. Family-dependent factors may alter the frequency of the seizure phenotype and the pattern of intergenerational repeat size changes, making the genotype-phenotype correlation complex.