'Complicated' autosomal dominant familial spastic paraplegia is genetically distinct from 'pure' forms
H. Meierkord, P. Nurnberg, A. Mainz, K. Marczinek, M. Mrug and J. Hampe
Neurologische Klinik, Universitatsklinikum Charite, Berlin, Germany.
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: Universitatsklinikum Charite, Humboldt-Universitat 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 Genethon 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.ACKG
