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April 1997

'Complicated' Autosomal Dominant Familial Spastic Paraplegia Is Genetically Distinct From 'Pure' Forms

Author Affiliations

From the Neurologische Klinik und Poliklinik (Drs Meierkord and Mainz) and the Institut für Medizinische Genetik (Drs Nürnberg, Marczinek, Mrug, and Hampe), Universitätsklinikum Charité, Berlin, Germany. Dr Mrug is now with the Institute of Haematology and Blood Transfusion, Prague, Czech Republic.

Arch Neurol. 1997;54(4):379-384. doi:10.1001/archneur.1997.00550160027011

Background:  The familial spastic paraplegias (FSPs) are hereditary neurodegenerative disorders with an unknown pathogenesis. Pure and complicated forms are currently differentiated on clinical grounds. To date, no linkage studies in complicated FSP have been reported, and candidate genes have not been suggested. Three different gene loci responsible for pure autosomal dominant FSP and 1 for pure autosomal recessive FSP recently have been found. This raises the question of whether the complicated forms may also be linked to any of these loci.

Objective:  To investigate whether complicated autosomal dominant FSP is allelic to any of the pure forms with defined loci.

Design:  Clinical characterization of a large kindred that included 4 generations and multipoint linkage analyses.

Setting:  Universitätsklinikum Charité, Humboldt-Universität Berlin, Neurologische Klinik und Poliklinik, Berlin, Germany.

Patients:  Twenty-six family members, 13 of whom were affected.

Results:  Thirteen members of a large family of 4 generations experienced a slowly progressive syndrome of spastic paraplegia. Hypomimia, bradykinesia, axial and limb rigidity, supranuclear gaze palsy, dysarthria, bladder and sphincter disturbances, cerebellar signs, and epilepsy were noted 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 transmission was compatible with an autosomal dominant mode of inheritance. The CAG-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 (AC)n dinucleotide repeat markers from the Généthon map demonstrated exclusion of all 4 FSP loci recently mapped by linkage to pure forms of FSP on chromosomes 14q, 2p, 15q, and 8.

Conclusions:  Complicated FSP in this family is not linked to any of the known pure FSP loci, including the recessive one. Therefore, the clinical differentiation of both forms still is of major relevance.

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