title: A novel X-linked four-repeat tauopathy with Parkinsonism and spasticity.
abstract: The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LOD(max) score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an approximately 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false-positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and four-repeat tau pathology, and defined a novel candidate gene locus spanning approximately 28 Mb from Xp11.2-Xq13.3.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA. pips@uw.edu
authors.forename: Parvoneh
authors.initials: P
authors.lastname: Poorkaj
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Mark
authors.initials: M
authors.lastname: Matsushita
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
authors.forename: Ali
authors.initials: A
authors.lastname: Samii
authors.forename: Sophia
authors.initials: S
authors.lastname: Kim
authors.forename: Nayiry
authors.initials: N
authors.lastname: Gazi
authors.forename: John G
authors.initials: JG
authors.lastname: Nutt
authors.forename: John
authors.initials: J
authors.lastname: Wolff
authors.forename: Dora
authors.initials: D
authors.lastname: Yearout
authors.forename: J Lynne
authors.initials: JL
authors.lastname: Greenup
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Steinbart
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D041321:Chromosomes, Human, X / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D050172:Genes, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications*; D024801:Tauopathies / Q000150:complications / Q000235:genetics*