COMPLICATED AUTOSOMAL-DOMINANT FAMILIAL SPASTIC PARAPLEGIA IS GENETICALLY DISTINCT FROM PURE FORMS

Background: The familial spastic paraplegias (FSPs) are hereditary neu rodegenerative disorders with an unknown pathogenesis. Pure and compli cated forms are currently differentiated on clinical grounds. To date, no linkage studies in complicated FSP have been reported, and candida te genes have not been suggested. Three different gene loci responsibl e for pure autosomal dominant FSP and 1 for pure autosomal recessive F SP recently have been found. This raises the question of whether the c omplicated forms may also be linked to any of these loci. Objective: T o investigate whether complicated autosomal dominant FSP is allelic to any of the pure forms with defined loci. Design: Clinical characteriz ation of a large kindred that included 4 generations and multipoint li nkage analyses. Setting: Universitatsklinikum Charite, Humboldt-Univer sitat Berlin, Neurologische Klinik und Poliklinik, Berlin, Germany. Pa tients: Twenty-six family members, 13 of whom were affected. Results: Thirteen members of a large family of 4 generations experienced a slow ly progressive syndrome of spastic paraplegia. Hypomimia, bradykinesia , axial and limb rigidity, supranuclear gaze palsy, dysarthria, bladde r and sphincter disturbances, cerebellar signs, and epilepsy were note d as additional features in some of the affected individuals. The mean age at onset was 20 years (range, 5-30 years), and the pattern of tra nsmission was compatible with an autosomal dominant mode of inheritanc e. The GAG-repeat expansions in the spinocerebellar ataxia type 1 and Machado-Joseph disease genes were not found. Linkage analysis with the use of a panel of (AG), dinucleotide repeat markers from the Genethon map demonstrated exclusion of all 4 FSP loci recently mapped by linka ge to pure forms of FSP on chromosomes 14q, 2p, 15q, and 8. Conclusion s: Complicated FSP in this family is not linked to any of the known pu re FSP loci, including the recessive one. Therefore, the clinical diff erentiation of both forms still is of major relevance.