CAG REPEAT EXPANSION IN AUTOSOMAL-DOMINANT PURE SPASTIC PARAPLEGIA LINKED TO CHROMOSOME 2P21-P24

CAG repeat expansions have been identified as the disease-causing dyna mic mutations in the coding regions of genes in several dominantly inh erited neurodegenerative disorders, including spinobulbar muscular atr ophy, Huntington's disease, dentatorubral-pallidoluysian atrophy, spin ocerebellar ataxia type 1, 2 and 6 and Machado-Joseph disease, The CAG repeat expansions are translated to elongated polyglutamine tracts an d an increased size of the polyglutamine tract correlates with anticip ation, the cardinal feature, seen in all these diseases, Autosomal dom inant pure spastic paraplegia (ADPSP) is a degenerative disorder of th e central motor system clinically characterized by slowly progressive and unremitting spasticity of the legs, hyperreflexia and Babinski's s ign. Like the established CAG repeat diseases ADPSP is characterized b y both inter-and intrafamilial variation and anticipation, Using the R epeat Expansion Detection (RED) method, we have analyzed 21 affected i ndividuals from six Danish families with the disease linked to chromos ome 2p21-p24, We found that 20 of 21 affected individuals showed CAG r epeat expansions versus two of 21 healthy spouses, demonstrating a str ongly statistically significant association between the occurrence of the repeat expansion and the disease (Fisher's test, P<10(-5)) suggest ing that a CAG repeat expansion is involved presumably as a dynamic mu tation in ADPSP linked to chromosome 2p21-p24, The size of the expansi on is estimated to be greater than or equal to 60 CAG repeat copies in the affected individuals, The CAG repeat expansion is very likely tra nslated and expressed as indicated by the detection of a polyglutamine -containing protein in an ADPSP patient.