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

Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically he terogeneous, neurodegenerative disorder characterized by spasticity and pro gressive weakness in the lower limbs. Anticipation has been suggested to oc cur and an association between expanded CAG/CTG repeats and AD-FSP linked t o the SPG4 locus (2p21-p24) has been described. In this study, 42 affected individuals from six SPG4 families were screened for expanded CAG/CTG repea ts using the repeat expansion detection (RED) method. Large RED products (r ange 180-240 nucleotides) corresponding in size to repeats at the ERDA1 loc us 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 famili es. Mean age at onset and index of severity were not significantly differen t between patients with or without expanded RED products. Furthermore, no a bnormal proteins were found by Western blot in 15 selected patient samples as compared with controls, using the 1C2 antibody, which detects long polyg lutamine stretches. Thus, in contrast to previous reports, our study provid es evidence against the hypothesis that a large translated CAG repeat expan sion is the basis of SPG4. We propose that mechanisms other than large path ogenic CAG/CTG repeats may account for the disease in the SPG4 families tes ted here. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.