Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, neurodegenerative disorder characterized by the progressive loss of neurons from the cerebellum, brain stem and spinocerebellar tracts (1, 2). Patients typically manifest with ataxia, dysarthria and bulbar findings consistent with the dysfunction of cranial nerves IX, X and XII (3, 4). Symptoms usually manifest between the third and fourth decade with death resulting from bulbar dysfunction after 10-20 years. Juvenileonset (age 18 years or less) has also been seen in some kindreds (5, 6). The gene for SCA1 has been mapped to chromosome 6p22-23 (7, 8). SCA1 is caused by the expansion of a polymorphic CAG repeat in the coding region of the SCA1 gene (9, 10). Normal SCA1 alleles carry 19-36 repeats while mutant alleles carry 41-81 repeats, with larger repeats found in juvenile-onset cases (11, 12). Normal alleles carry CAG repeats interrupted by a single region with 1-3 CAT trinucleotides while expanded alleles carry uninterrupted repeats (12). We now describe a normal SCA1 allele with an expanded but novel CAG repeat configuration. The characterization of this unique allele demonstrates that a molecular diagnosis of SCA1 cannot be made solely on the basis of repeat size and indicates that the molecular determinant of a disease allele may be the length of the longest uninterrupted CAG repeat rather than total repeat size.

The pedigree of the investigated family is shown in Figure 1. The proband (II-1) was a 6 year 2 month old female with mild developmental delay, truncal ataxia initiating at age 2 years, head titubation and scanning speech, with no indication of dysarthria or nystagmus. Cranial nerve function was virtually intact. However, the absence of reflexes and the finding of decreased nerve conduction velocities were consistent with a peripheral neuropathy. Examination of the proband's parents failed to reveal signs of neurological impairment. There was no other family history of neurological disorders. To rule out a diagnosis of juvenile-onset SCA1 in the proband, the SCA1 CAG repeat was amplified by PCR using the primers Rep-1 and Rep-2, flanking the repeat (9). This analysis demonstrated that the proband carried a normal allele with 28 CAG repeats and an expanded allele with 44 CAG repeats (Fig. 2, lane 1). The presence of an SCA1 allele with greater than 36 repeats was clearly consistent with a diagnosis of SCA1 (11) but inconsistent with the proband's early onset of symptoms. In juvenile-onset SCA1, the size of the CAG repeat expansion is typically in the upper end of the affected size range (9, 11). For example, an allele with 81 CAG repeats has been reported in a patient with an age-of-onset of 4 years