No evidence for long CAG/CTG repeats in families with spastic paraplegia linked to chromosome 2p21-24.

Abstract Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically heterogeneous, neurodegenerative disorder characterized by spasticity and progressive weakness in the lower limbs. Anticipation has been suggested to occur and an association between expanded CAG/CTG repeats and AD-FSP linked to the SPG4 locus (2p21-p24) has been described. In this study, 42 affected individuals from six SPG4 families were screened for expanded CAG/CTG repeats using the repeat expansion detection (RED) method. Large RED products (range 180–240 nucleotides) corresponding in size to repeats at the ERDA1 locus were detected in eight patients and at the CTG 18.1 locus in one patient. The large ERDA1 repeats did not segregate with the disorder within families. Mean age at onset and index of severity were not significantly different between patients with or without expanded RED products. Furthermore, no abnormal proteins were found by Western blot in 15 selected patient samples as compared with controls, using the 1C2 antibody, which detects long polyglutamine stretches. Thus, in contrast to previous reports, our study provides evidence against the hypothesis that a large translated CAG repeat expansion is the basis of SPG4. We propose that mechanisms other than large pathogenic CAG/CTG repeats may account for the disease in the SPG4 families tested here.