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.

Figure 1. The four-generation pedigree of the XPDS family

A diagonal line denotes individuals who are deceased. Haplotypes are shown for all pedigree members from whom DNA was obtained. The apparent disease-related haplotype region is boxed. Haplotype markers are listed to the right of the genotype for subject II-9 and approximate distances between markers are listed to the right. Secondary genotyping defined the critical region between markers DXS8042 and DXS1216; DX1216 is located between markers DXS991 and DXS986.

Figure 2

Multipoint linkage analysis performed with GENEHUNTER-IMPRINTING using 23 markers spanning the X chromosome.

Figure 3. Immunostaining characteristics of plaque-like pathology in the striatum of the XPDS autopsied case

AT8, Gallyas, and RD4 (4-repeat tau specific antibody) stain plaque-like pathology in the striatum (A–D). Double immunolabeling with GFAP for astrocytes and AT8 demonstrate close association of glia and tau pathology (E) and double labeling of glial processes (F, arrow). Immunostaining with the 3-repeat tau specific antibody RD3 fails to label this pathology in the striatum (G), although age-associated neurofibrillary tangle and neuritic plaque pathology in the hippocampus was immunopositive (H).