title: Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation.
abstract: The most common form of autosomal dominant hereditary spastic paraparesis (HSP), SPG4, is caused by mutations in the spastin gene on chromosome 2p. This disease is characterized by intra- and interfamilial phenotypic variation. To determine the predictive values of clinical signs and symptoms in SPG4, we examined 43 members of a large pedigree with autosomal dominant HSP. We then identified the genetic etiology of the disorder in this family, a novel nonsense mutation in exon 1 of spastin, carried by 24 of the examined family members. The best clinical predictors of positive gene status were the presence of hyperreflexia in the lower extremities, >2 beats of ankle clonus, pes cavus, bladder symptoms and increased tone in the legs. The mean age of onset was 32.2 +/- 7.4 years, but the age of onset was earlier in children from 10 of 12 child-parent gene-positive pairs, with a mean difference of 10.8 +/- 3.3 years. The finding of leg weakness was especially common in older-onset affected family member with leg hyperreflexia. These results suggest that specific clinical signs and symptoms may be of value in differentiating individuals affected with SPG4 from family members with nonspecific neurological findings.
authors.affiliation: Department of Neurology, University of Alabama at Birmingham and the Birmingham Veterans Administration Medical Center, Birmingham, Alabama 35249-7340, USA. nicholas@uab.edu
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Nicholas
authors.forename: Elizabeth
authors.initials: E
authors.lastname: O'Hearn
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holmes
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D002135:Calcium-Binding Proteins / Q000235:genetics*; D042622:DNA Repeat Expansion / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020336:Paraparesis, Spastic / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000074181:Spastin; D014743:Videotape Recording
chemical_list: D002135:Calcium-Binding Proteins; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human