CAG repeat expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24

CAG repeat expansions have been identified as the disease-causing dynamicmutations in the coding regions of genes in several dominantly inheritedneurodegenerative disorders, including spinobulbar muscular atrophy,Huntington's disease, dentatorubral-pallidoluysian atrophy, spinocerebellarataxia type 1, 2 and 6 and Machado-Joseph disease. The CAG repeatexpansions are translated to elongated polyglutamine tracts and anincreased size of the polyglutamine tract correlates with anticipation, thecardinal feature, seen in all these diseases. Autosomal dominant purespastic peraplegia (ADPSP) is a degenerative disorder of the central motorsystem clinically characterized by slowly progressive and unremittingspasticity of the legs, hyperreflexia and Babinski's sign. Like theestablished CAG repeat diseases ADPSP is characterized by both inter- andintrafamilial variation and anticipation. Using the Repeat ExpansionDetection (RED) method, we have analyzed 21 affected individuals from sixDanish families with the disease linked to chromosome 2p21-p24. We foundthat 20 of 21 affected individuals showed CAG repeat expansions versus twoof 21 healthy spouses, demonstrating a strongly statistically significantassociation between the occurrence of the repeat expansion and the disease(Fisher's test, P < 10(-5)) suggesting that a CAG repeat expansion isinvolved presumably as a dynamic mutation in ADPSP linked to chromosome2p21-p24. The size of the expansion is estimated to be > or = 60 CAGrepeat copies in the affected individuals. The CAG repeat expansion is verylikely translated and expressed as indicated by the detection of apolyglutamine-containing protein in an ADPSP patient.